An inhalable gallium-polyphenol nanoparticle blocks bacterial electron transport chain and signal transduction for anti-biofilm therapy

Bacterial biofilms have become an escalating global health threat due to their persistent infections and antimicrobial resistance. Conventional antibacterial approaches often fail to eliminate biofilms due to biofilm complexity involving both metabolic activity and intercellular communications. Herein, gallium-quercetin nanoparticles (GEQ NPs) are designed as a multimodal nanoplatform to combat recalcitrant <i>Pseudomonas aeruginosa</i> biofilm infections through concurrent electron transport chain (ETC) blockage and signal transduction disruption. GEQ NPs are prepared through coordination-driven self-assembly of Ga³⁺, quercetin, and ε-poly-L-lysine, which specifically dissociate in acidic infection microenvironments. The released Ga³⁺ acts as an iron analog to disrupt bacterial ETC by competitively inhibiting Fe-dependent enzymes, causing ATP depletion and protein synthesis arrest. Simultaneously, quercetin suppresses multiple biofilm-associated signal transduction systems including quorum sensing, chemotaxis system, and two-component system. This dual-targeting strategy synergistically disrupts biofilm-embedded bacterial energy metabolism and signal transduction. In a murine invasive lung infection model, nebulization-inhalable GEQ NPs demonstrates superior anti-biofilm efficiency <i>in vivo</i>.